Metabolic adaptations rewire CD4+ T cells in a subset-specific manner in human critical illness with and without sepsis

Abstract Metabolic and immunologic dysfunction, including pathological CD4 + T cell immunosuppression, are archetypal in critical illness, but whether these factors are mechanistically linked remains incompletely defined. Here we characterized the metabolic properties of human CD4 + T cells from critically ill patients with and without sepsis and healthy adults. CD4 + T cells in critical illness showed subset-specific metabolic plasticity, with regulatory T (T reg ) cells preferentially acquiring glycolytic capacity that associated with sustained cellular fitness and worsened clinical illness. Adapted T reg cells were more metabolically flexible and stabilized suppressive markers FOXP3 and TIGIT under mitochondrial stress. Single-cell transcriptomics suggested reactive oxygen species (ROS) and kynurenine metabolism as drivers of T reg cell remodeling. Subsequent inhibition of ROS and kynurenine metabolism attenuated glycolytic adaptation and suppressive rewiring, respectively, in T reg cells. These findings indicate that metabolic dysfunction was a contributor to CD4 + T cell remodeling in critical illness and suggest avenues to restore effective immunity.